Adverse Pregnancy Outcomes Associated with Endometriosis and Its Influencing Factors

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Introduction
Endometriosis [1] refers to the presence of endometrial tissue (glandular and mesenchymal) in the uterine cavity outside of the overlying endometrium and uterus, with recurrent bleeding and subsequent pain. It causes infertility and growth of nodules. Endometriosis has a high prevalence among women of childbearing age, and the lesion recedes after menopause. Te disease is aggressive, recurrent, and sex hormone-dependent [2,3]. Previous studies have shown that endometriosis increased the risk of several adverse pregnancy outcomes, such as preterm delivery, placenta previa, stillbirth, placental abruption, postpartum hemorrhage, and gestational diabetes [3,4]. Moreover, Broi et al. [5] and Vercellini et al. [6] have reported an increased risk of hypertensive disorders during pregnancy. Te size and depth of the peritoneal and ovarian lesions, the degree and extent of adhesion of the ovaries and fallopian tubes, and the magnitude of closure of the rectum and uterine pits are used for endometriosis classifcation. Te most well-accepted notion of its pathophysiology is endometrial implantation [4].
Pelvic pain is observed in 70-80% of the patients, including menstrual pain, chronic pelvic pain, painful intercourse, and anal cramps, infertility is found in 40%-50%, and 17-44% develop a pelvic mass (endometriotic cyst). It afects all pelvic tissues and organs, most notably the ovaries, uterine and rectal recesses, and uterosacral ligaments [5]. Periodic bleeding from the ectopic foci stimulates infammatory reactions in the surrounding tissues, leading to adhesions in the pelvic cavity, which in severe cases compromises the peristalsis of the fallopian tubes or even leads to tubal obstruction. Te preferred treatment option for endometriosis combined with infertility is laparoscopic surgery, which allows the diagnosis of the disease, removal of the lesion, and breakdown of adhesions, so as to improve the conception rate. However, the postoperative fertility rate remains unsatisfactory. In traditional Chinese medicine (TCM), the main pathogenesis of endometriosis is the stasis of blood blocking the ramus and the uterus. Endometriosis develops due to congenital defciency of kidney essence, liver qi stagnation, and cold clotting of blood in the meridians. Te patient's congenital defciency of kidney essence, loss of both yin and yang, and inappropriate storage and drainage of the uterus result in stasis of the blood in the uterus. Te patient's negative emotions, stagnant liver qi, and insufcient kidney yang lead to impaired warmth and aggravate the stasis of menstrual blood. Clinical treatments include surgery, medication, interventional therapy, herbal medicine, and adjuvant therapy (e.g., assisted reproductive technology treatment), so as to eliminate the lesions, reduce pain, ameliorate fertility, and avoid recurrence [6,7].
Related research suggests a strong correlation between rectovaginal endometriosis and placenta previa [8]. Endometriosis may result in an increased risk of pregnancy complications [9], such as placenta previa, preterm delivery, hypertensive disorders of pregnancy, small gestational age, placental abruption, and postpartum hemorrhage. It is also considered to be associated with menstrual blood refux [10]. Endometriosis is suggested to cause local immune and infammatory responses via the production of cytokines, immune factors, and prostaglandins, resulting in a signifcant elevation of interleukin 1 and angiogenic factors in the peritoneal cavity, facilitating the adhesion of ectopic endometrial cells to the peritoneum, angiogenesis, and proliferation of ectopic endometrial lesions [11]. Te signifcant elevation of cyclooxygenase 2, prostaglandin E and cytokines due to persistent immune, and infammatory responses in the peritoneal cavity of patients with endometriosis may give rise to myometrial contraction and premature cervical maturation during pregnancy [12]. Tese aggravated infammatory responses and growth factors on the uterine meconium and trophectoderm may also trigger adverse pregnancy outcomes.
However, the contributory factors of endometriosis on perinatal outcomes are still poorly understood [13]. To this end, this study was undertaken to investigate the adverse pregnancy outcomes associated with endometriosis and its infuencing factors, so as to provide relevant references for subsequent clinical treatment.

Participants.
A total of 188 endometriosis patients who delivered at our hospital between June 2018 and January 2021 were screened for eligibility and included in the research group, whereas a control group of 188 nonendometriosis women who delivered at our hospital during the same period was included. Te patients in the study group had endometriosis before pregnancy or ovarian endometriosis in early pregnancy, and they were treated accordingly.
Te original sample size calculation estimated that 90 patients in each group would be needed to detect a 3-point diference between groups in a 2-sided signifcance test with a power of 0.8 and an alpha error level of 0.05.
Undersigned informed consent was obtained from the eligible patients prior to enrollment. Te study protocol was approved by the Hospital Ethics Committee, and all processes complied with the Declaration of Helsinki ethical guidelines for clinical research.

Inclusion and Exclusion Criteria
(1) Patients in the study group are those with pelvic endometriosis confrmed by histological examination [14]; (2) participants in the control group are those without confrmed endometriosis or any related ultrasound signs; (3) age ≤38 years, follicle-stimulating hormone <10 U/L, and endometrial thickness >8 mm on the day of progesterone conversion; (4) the patients were diagnosed with stage II EMT by laparoscopic surgery; and (5) prior to FET, vaginal ultrasound and hysteroscopy were performed without uterine malformations, endometrial polyps, and uterine adhesions.

Outcome Measures.
Outcome measures include gestational age, mode of delivery, luteal support, and adverse pregnancy outcomes (preterm delivery, hypertensive disorders in pregnancy, gestational diabetes mellitus, placenta previa, placental abruption, and fetal growth restriction).

Preterm Delivery.
Delivery was performed before 37 weeks of gestation.

Hypertensive Disorder in Pregnancy.
It includes gestational hypertension and preeclampsia. Gestational hypertension refers to an increase in blood pressure of ≥140/ 90 mmHg after 20 weeks of gestation in a woman with previously normal blood pressure. Preeclampsia is gestational hypertension with proteinuria (≥300 mg/24 h).

Gestational Diabetes.
Gestational diabetes is diagnosed when any of the three values is met at 24-26 weeks of pregnancy, namely, fasting blood glucose ≥5.1 mmol/L, ≥10 mmol/L one hour after drinking sugar water, or ≥8.5 mmol/L two hours after drinking sugar water.  Evidence-Based Complementary and Alternative Medicine

Placental Abruption.
Bleeding at the meconiumplacenta interface results in partial or complete detachment of the placenta before delivery.

Fetal Growth Restriction.
Fetal birth weight is lower than two standard deviations from the mean weight for the same gestational age or less than the 10th percentile of the normal weight for the same age.

Statistical Analysis.
Logistic regression was used to analyze the adverse pregnancy outcomes and infuencing factors associated with endometriosis, and SPSS 22.0 software was used to process the data and statistical analyses.
Te measurement data were expressed as (mean ± standard deviation) and analyzed by the independent sample t-test. Count data were expressed as number of cases (%) and analyzed by the chi-square test. P < 0.05 suggested that the diference was statistically signifcant.

Discussion
Endometriosis is the presence of the endometrial tissue (glandular and mesenchymal) in the uterine cavity outside the overlying endometrium and uterus [15]. Te diagnosis of endometriosis requires the laparoscopic examination of visible pelvic lesions and biopsies of the lesions [16]. Te increased use of human-assisted reproductive technologies has signifcantly boosted pregnancy success rates in patients with endometriosis, and there is also an escalating incidence of adverse pregnancy outcomes due to adverse reactions caused by endometriosis [17]. Endometriosis may lead to pregnancy failure or complications in late pregnancy. Te local immune and infammatory response to endometriosis signifcantly increases the levels of intraperitoneal IL-1β and angiogenic factors, which favor ectopic endometrial cell adhesion, proliferation, and angiogenesis. Tus, the local immunological and infammatory response to endometriosis has a long-term impact on pregnancy and progesterone resistance, irregular uterine contractions, and thickening of the uterine junctional zone all threaten embryo implantation. Te relationship between endometriosis and poor pregnancy outcomes, however, remains uncertain. Previous research has implicated endometriosis with the development of unfavorable pregnancy outcomes [18]. Previous studies suggest that chronic infammation, uterine hormone-resistant endometrium, and the vascularized environment are associated with complications during pregnancy. In addition, abnormalities in the endometrium and the junctional zone at the molecular and functional levels lead to impaired endometrial growth, maturation and ecdysis, endometrial tolerance, defective spiral artery remodeling, and deep placental defects [19]. Preeclampsia is characterized by abnormal vascular remodeling, which is linked to a variety of pregnancy problems, including premature birth and fetal development limitation. As a result, it is theorized that placental anomalies are associated with an increased risk of placental problems and that endometriosis initiates a persistent pelvic infammatory process. Te increased number of prostaglandins and cytokines in endometriosis patients' peritoneal fuid increases myometrial contraction and cervical maturation, resulting in premature birth [22,23]. In addition, alterations in the frequency and amplitude of uterine contractions in women with endometriosis cause dysfunction of the uterine tissues, which contributes to the increased risk of placenta previa. Due to extensive pelvic adhesions, placenta previa may also hinder placental migration from the intrauterine aperture. Te higher incidence of placenta previa in endometriosis patients treated surgically before pregnancy is attributed to severe endometriosis or a high incidence of recurrence. Te association between preconception surgery for endometriosis and the risk of placenta previa has been marginally explored [24,25].
Surgery is currently the main treatment modality for endometriosis-related infertility, and laparoscopic surgery can increase the pregnancy rate to 46.09%. Laparoscopic surgery is currently the gold standard for the diagnosis and treatment of endometriosis, with minimal gas trauma and short healing time, during which the ectopic foci visible to the naked eye can be removed and the mutual adhesions between tissues can be separated, so as to restore the anatomical structure of the pelvis. One of the causes of infertility in patients is the altered pelvic microenvironment, and intraoperative saline irrigation of the pelvis to improve its microenvironment is the major merit of laparoscopic surgery. However, laparoscopic surgery is insufcient for the removal of microscopic lesions and atypical ectopic lesions, Evidence-Based Complementary and Alternative Medicine so postoperative adjuvant medication is required. TCM classifes endometriosis as "infertility" and "menstrual disorders" according to its symptoms. According to the ancient medical books of TCM, if the pain occurs before menstruation, it is a factual pain and the pain will be relieved if the menstrual blood is discharged on time. If the pain occurs after menstruation and the pain persists after the discharge of menstrual blood, it is defcient pain. Diagnosis of the specifc disease requires the clinical assessment of the patient's clinical symptoms.
Te results of this study showed that there was no signifcant diference in the risk of events such as miscarriage, ectopic pregnancy, termination of pregnancy, and fetal death between the two groups, and the diferences in hypertensive disorder in pregnancy, gestational diabetes, placental abruption, fetal growth restriction, and luteal support between the two groups also failed to meet the statistical standard (P > 0.05), while the incidence of cesarean delivery, preterm delivery, and placenta previa differed signifcantly between the two groups (1.92 (95% CI 1.33-2.85), 2.43 (95% CI 1.05-5.58), and 4.51 (95% CI 1.23-16.50)), which may be attributed to the imbalance of progesterone receptor subtype ratios in patients with endometriosis, causing progesterone resistance [24] and abnormal autoimmune response, inducing an increase in abdominal macrophages and the secretion of a large number of cytokines [25], such as prostaglandin F2α. Prostaglandin F2α levels are signifcantly elevated in the peritoneal fuid of patients with endometriosis relative to normal women, and prostaglandin F2α binds to the receptor and activates nucleic acid endonucleases that break DNA, leading to decreased blastocyst formation and quality. Multiple factors interact with each other to disturb the normal implantation and development of the embryo, thus causing stillbirth [26]. Long-term infammatory stimulation in patients with endometriosis interferes with the normal contraction frequency and amplitude of the uterus, and endometriosis causes pelvic adhesions, leading to placenta previa [27]. Endometriosis pelvic adhesions reduce the amplitude of contraction of the myometrium, compromise postpartum uterine contraction, and increase the risk of postpartum hemorrhage [28]. Endometrial structural and functional changes, progesterone resistance, local estrogen and oxidative stress responses, and variations in infammatory mediators and apoptotic markers all raise the risk of early placental abruption [29]. Patients herein were diagnosed histologically with endometriosis, which reduced the risk of misclassifcation.
Swedish national research encompassing over 1.4 million singleton births found that women with endometriosis had a greater risk of preterm delivery, preeclampsia, placental problems, and cesarean delivery, but no link between endometriosis and fetal growth limitation was found. According to an Italian study, women with endometriosis are twice as likely to have a preterm delivery. Te current study's fndings are consistent with the prior research that revealed a link between endometriosis and placenta previa [30]. However, it is worth noting that the interaction Evidence-Based Complementary and Alternative Medicine between adverse pregnancy outcomes, such as placenta previa, and hypertensive disorders in pregnancy increases the risk of cesarean delivery and fetal growth restriction and may compromise the accuracy of the association between endometriosis and adverse pregnancy outcomes [31]. Furthermore, there are diferences in the statistical methods used in diferent studies and the sample size, which also afect the research conclusion. Te present study is a single-center retrospective study, lacking a multicenter large sample control, and there are limitations in the representation of the association between endometriosis and pregnancy outcome, and further prospective multicenter cohort studies are needed to investigate the impact of endometriosis on maternal and infant outcomes. Tis study lacks analyses of the long-term efects on neonates. In future studies, the long-term follow-up of neonates is needed to more comprehensively describe the efects of endometriosis on neonatal outcomes. Te present study lacks the study of the molecular mechanisms associated with endometriosis and adverse pregnancy outcomes, and the interaction mechanisms between the two will be further elucidated at the molecular level.

Conclusion
Endometriosis is an infuential factor in adverse pregnancy outcomes and results in a high risk of preterm delivery, placenta previa, and cesarean delivery in patients. Mutual interactions exist among adverse pregnancy outcomes and thus require vigilance and appropriate management.

Data Availability
No data were used to support this study.

Conflicts of Interest
All authors declare that they have no conficts of interest.

Authors' Contributions
Li Xie drafted and revised the manuscript. Yuanjie Qi, Hua Li, and Li Chen conceived and designed this article and were in charge of syntax modifcation and revision of the manuscript. All the authors have read and agreed to the fnal version of the manuscript. Te authors Li Xie and Yuanjie Qi were contributed equally to this work.